Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Papillary carcinoma of thyroid: Classical and variants

Papillary carcinoma, the commonest primary cancer of thyroid, exhibits a broad morphological spectrum. In this review, the clinicopathological features of papillary carcinoma, classical and its variants (follicular, solid, cribriform, variant with exuberant nodular fasciitis-like stroma, encapsulated, diffuse sclerosing, diffuse follicular, tall cell, columnar cell, oxyphil cell, c> occult, latent and microcarcinoma) are summarized

Bacillary angiomatosis. A ((new)) disease with a broadening clinicopathologic spectrum

Bacillary angiomatosis (BA) is a reactive vasoproliferative lesion occurring almost exclusively in immunocompromised individuals in response to infection by a bacillus closely related to Rochalimaea quintana. The commonest site of involvement is the skin, in the form of multiple erythematous nodules, but bacillary angiomatosis can also present in a wide variety of sites such as soft tissues, bone, lymph node, liver and spleen. Some patients may present with persistent fever and bacteraemia. Bacillary angiomatosis is characterized histologically by proliferation of blood vessels lined by plump endothelium, associated with an interstitial eosinophilic or amphophilic material formed by aggregated bacilli, best demonstrated by the Warthin- Starry stain. A heavy infiltrate of neutrophils is frequently, but not invariably, present. In the liver and spleen, there may be in addition features of peliosis. It is important to be able to diagnose bacillary angiomatosis correctly because prompt treatment with antibiotics is potentially life-saving

The family of epithelioid vascular tumors

Vascular tumors characterized by proliferation of epithelioid (histiocytoid) endothelial cells with abundant eosinophilic hyaline cytoplasm span a broad spectrum of histologic appearances and behaviour. They can occur in a wide variety of sites, such as soft tissues, skin, bone and visceral organs. On the benign end are the epithelioid hemangiomas (angiolymphoid hyperplasia with eosinophilia), which are composed predominantly of well formed vascular channels, and are frequently accompanied by an infiltrate of lymphocytes and eosinophils. In the literature, they have often been confused with Kimura's disease, an idiopathic allergic-inflammatory condition. There have also been controversies as to whether these lesions are neoplastic or reactive. In the middle of the spectrum are the borderline or low grade malignant epithelioid hemangioendotheliomas, characterized by isolated, cords and nests of epithelioid endothelial cells disposed in a hyaline or myxoid matrix; cytoplasmic vacuoles are common. However, the morphologic variations on this theme are very wide rendering recognition of these tumors difficult sometimes. On the malignant end are highly aggressive epithelioid angiosarcomas showing predominantly solid growth and significant nuclear pleomorphism. In addition, there are also cases showing histologic features straddling the borderline areas between the above three defined categories. In this review, the broad morphologic appearances of these epithelioid vascular tumors are discussed and illustrated

Natural killer cell malignancies: clinicopathologic and molecular features

Malignancies of natural killer (NK) cells h ave increasingly been recognized as distinct clinicopathological entities. The tumor cells are characterized by an immunophenotype of CD2+, surface CD3-, cytoplasmic CD3e+, and CD56+. The T cell receptor gene is in germline configuration, and a consistent association with Epstein-Barr virus is demonstrable. Pa t h o l o g i c a l l y, the tumor cells show variable cytological appearances, with frequent angioinvasion and angiocentricity associated with zonal necrosis. Clinically, most cases affect the nasal cavity or other parts of the upper aerodigestive tract, and are referred to as nasal NK cell lymphoma. A minority involve extranasal sites such as the skin, gastrointestinal tract and testis, and are often referred to as ex t r a n a s a l NK cell lymphoma. A particularly aggressive form presents fulminantly as disseminated disease, sometimes with a leukemic phase, and is referred to as aggressive NK cell lymphoma/leukemia. Cytogenetic and molecular analysis have shown DNA losses at chromosomes 6q, 11q, 13q and 17p to be recurrent aberrations in NK cell malignancies. Frequent DNA gains are also found in chromosomes 1p, 6p, 11q, 12q, 17q, 19p, 20q, and Xp. These regions of DNA losses and gains should be targets for further inve s t i gation in order to understand the molecular pathogenesis of this lymphoma. Finally, optimal treatment modalities need to be determined, as all subtypes of NK cell malignancies are associated with a poor prognosis

Experience with the management of ovarian germ cell tumors in Chinese patients

Treatment results of 37 consecutive patients with primary ovarian germ cell tumors (OGCTs) were analyzed. Thirty-three were referred after initial laparotomy and four were first seen at relapse. Four patients with stage I dysgerminoma and grade 1 immature teratoma were observed after operation without recurrence. There was also no relapse in eight patients with dysgerminoma given postoperative irradiation (whole abdomen, median 30 Gy). Twenty-five patients (3 dysgerminomas, 11 immature teratomas, 9 endodermal sinus tumors, and 2 mixed germ cell tumors) received short-term cis-platinum- based chemotherapy. Six out of eight measurable tumors treated by chemotherapy had complete remission. Complete follow-up information was obtained in 35 out of 37 patients. The 4-year actuarial survival rates of the whole group and those referred immediately after initial surgery were 94.1 and 100%, respectively. cis-Platinum was substituted by carboplatin in eight cases but this did not affect treatment result. Nonetheless, deaths occurred in two of four patients referred at relapse with extensive disease and initially treated with suboptimal regimens. Chemotherapy-induced side effects were common but mostly tolerable and were related to cis-platinum and bleomycin. The results of this series show that cis-platinum-based chemotherapy is so effective that nearly 100% cure can be achieved in OGCTs and suggest that it is important to institute optimal chemotherapy from the start. On the other hand, common side effects of treatment and possible late toxicities make it desirable for future studies to see whether chemotherapy intensity could be reduced in patients with good prognosis. © 1994 by Academic Press, Inc.Link_to_subscribed_fulltex